A retrospective study on the efficacy of Roxadustat in peritoneal dialysis patients with erythropoietin hyporesponsiveness.

BACKGROUND/AIMS: Roxadustat, an oral medication for treating renal anemia, is a hypoxia-inducible factor prolyl hydroxylase inhibitor used for regulating iron metabolism and promoting erythropoiesis. To investigate the efficacy and safety of roxadustat in patients undergoing peritoneal dialysis (PD) with erythropoietin hyporesponsiveness. METHODS: Single-center, retrospective study, 81 PD patients (with erythropoietin hyporesponsiveness) were divided into the roxadustat group (n = 61) and erythropoiesis-stimulating agents (ESAs) group (n = 20). Hemoglobin (Hb), total cholesterol, intact parathyroid hormone (iPTH), brain natriuretic peptide (BNP), related indicators of cardiac function and high-sensitivity C-reactive protein (hs-CRP) were collected. Additionally, adverse events were also recorded. The follow-up period was 16 weeks. RESULTS: The two groups exhibited similar baseline demographic and clinical characteristics. At baseline, the roxadustat group had a mean Hb level of 89.8 ± 18.9 g/L, while the ESAs group had a mean Hb level of 95.2 ± 16.0 g/L. By week 16, the Hb levels had increased to 118 ± 19.8 g/L (p < 0.05) in the roxadustat group and 101 ± 19.3 g/L (p > 0.05) in the ESAs group. The efficacy of roxadustat in improving anemia was not influenced by baseline levels of hs-CRP and iPTH. Cholesterol was decreased in the roxadustat group without statin use. An increase in left ventricular ejection fraction and stabilization of BNP were observed in the roxadustat group. CONCLUSION: For PD patients with erythropoietin hyporesponsiveness, roxadustat can significantly improve renal anemia. The efficacy of roxadustat in improving renal anemia was not affected by baseline levels of hs-CRP0 and iPTH.

Medium-Dose Formoterol Attenuated Abdominal Aortic Aneurysm Induced by EPO via ß2AR/cAMP/SIRT1 Pathway.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease but effective drugs for treatment of AAA are still lacking. Recently, erythropoietin (EPO) is reported to induce AAA formation in apolipoprotein-E knock out (ApoE-/-) mice but an effective antagonist is unknown. In this study, formoterol, a ß2 adrenergic receptor (ß2AR) agonist, is found to be a promising agent for inhibiting AAA. To test this hypothesis, ApoE-/- mice are treated with vehicle, EPO, and EPO plus low-, medium-, and high-dose formoterol, respectively. The incidence of AAA is 0, 55%, 35%,10%, and 55% in these 5 groups, respectively. Mechanistically, senescence of vascular smooth muscle cell (VSMC) is increased by EPO while decreased by medium-dose formoterol both in vivo and in vitro, manifested by the altered expression of senescence biomarkers including phosphorylation of H2AXserine139, senescence-associated ß-galactosidase activity, and P21 protein level. In addition, expression of sirtuin 1 (SIRT1) in aorta is decreased in EPO-induced AAA but remarkably elevated by medium-dose formoterol. Knockdown of ß2AR and blockage of cyclic adenosine monophosphate (cAMP) attenuate the inhibitory role of formoterol in EPO-induced VSMC senescence. In summary, medium-dose formoterol attenuates EPO-induced AAA via ß2AR/cAMP/SIRT1 pathways, which provides a promising medication for the treatment of AAA.

The Use of Anemia Control Model Is Associated with Improved Hemoglobin Target Achievement, Lower Rates of Inappropriate Erythropoietin Stimulating Agents, and Severe Anemia among Dialysis Patients.

INTRODUCTION: The Anemia Control Model (ACM) is a certified medical device suggesting the optimal ESA and iron dosage for patients on hemodialysis. We sought to assess the effectiveness and safety of ACM in a large cohort of hemodialysis patients. METHODS: This is a retrospective study of dialysis patients treated in NephroCare centers between June 1, 2013 and December 31, 2019. We compared patients treated according to ACM suggestions and patients treated in clinics where ACM was not activated. We stratified patients belonging to the reference group by historical target achievement rates in their referral centers (tier 1: <70%; tier 2: 70-80%; tier 3: >80%). Groups were matched by propensity score. RESULTS: After matching, we obtained four groups with 85,512 patient-months each. ACM had 18% higher target achievement rate, 63% smaller inappropriate ESA administration rate, and 59% smaller severe anemia risk compared to Tier 1 centers (all p < 0.01). The corresponding risk ratios for ACM compared to Tier 2 centers were 1.08 (95% CI: 1.08-1.09), 0.49 (95% CI: 0.47-0.51), and 0.64 (95% CI: 0.61-0.68); for ACM compared to Tier 3 centers, 1.01 (95% CI: 1.01-1.02), 0.66 (95% CI: 0.63-0.69), and 0.94 (95% CI: 0.88-1.00), respectively. ACM was associated with statistically significant reductions in ESA dose administration. CONCLUSION: ACM was associated with increased hemoglobin target achievement rate, decreased inappropriate ESA usage and a decreased incidence of severe anemia among patients treated according to ACM suggestion.

Full Correction of Posttransplant Anemia Is Associated With Stabilized Cardiac Dimensions Among Kidney Transplant Recipients: A Prospective Randomized Controlled Trial.

OBJECTIVES: Posttransplant anemia might be associated with cardiovascular morbidity and increased mortality. To our knowledge, the debate on anemia correction has neither been revisited nor decided definitively. We aimed to assess the effects of full correction of posttransplant anemia on the cardiovascular system and quality of life among renal transplant recipients with stable graft function who were using erythropoietin-stimulating agents. MATERIALS AND METHODS: We enrolled 247 kidney recipients with stable graft function to be assessed for anemia. Eligible patients were randomized to achieve targeted hemoglobin of 11 to 12 g/dL (group 1, n = 183) or of 13 to 15 g/dL (group 2, n = 64) with the use of erythropoietin-stimulating agents. Patients underwent monthly clinical and laboratory evaluations of kidney graft function. Quality of life and echocardiography were assessed at study start and at 12 months. RESULTS: The 2 groups were comparable regarding pretransplant characteristics. In group 2, we observed comparable posttransplant complications (P > .05) but better graft function at 6 months and better cardiac indexes at 1 year of the study (P < .05). At 12 months, quality of life had improved after full correction of posttransplant anemia in the renal transplant recipients who received erythropoietinstimulating agents. CONCLUSIONS: Full correction of posttransplant anemia in renal transplant recipients was associated with improved quality of life and cardiac indexes without an effect on cardiovascular comorbidity.

Evaluating the Safety and Efficacy of Erythropoietin Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review and Meta-Analysis.

BACKGROUND: Erythropoietin (EPO) is a proposed drug for the treatment of neonatal hypoxic-ischemic encephalopathy (HIE). Multiple studies have linked its use, either as a monotherapy or in conjunction with therapeutic hypothermia (TH), with improved neonatal outcomes including death and neurodisability. However, there is also evidence in the literature that raises concerns about its efficacy and safety for the treatment of neonatal encephalopathy (NE). METHODS: We searched MEDLINE, Cochrane CENTRAL, and Embase for both observational studies and randomized controlled trials (RCTs) investigating the effectiveness of EPO in treating NE. Only studies in which at least 300 U/kg of EPO was used and reported any one of the following outcomes: death, death or neurodisability, and cerebral palsy, were included. RESULTS: Seven studies with 903 infants with the diagnosis of NE were included in our meta-analysis. EPO did not reduce the risk of death or neurodisability (risk ratio 0.68 [95% confidence interval [CI]: 0.43 to 1.09]) (P = 0.11). Similarly, the risk of cerebral palsy was not reduced by the administration of EPO (risk ratio 0.68 [95% CI: 0.33 to 1.40]) (P = 0.30). The risk of death was also not reduced at any dose of EPO regardless of the use of TH. CONCLUSIONS: The results of our meta-analysis do not support the use of EPO for the treatment of neonatal encephalopathy. However, future large-scale RCTs are needed to strengthen these findings.

Fatigue visual analogue scale score correlates with quality of life in cancer patients receiving epoetin alfa (Sandoz) for chemotherapy-induced anaemia: The CIROCO study.

PURPOSE: Available tools to measure fatigue and health-related quality of life (HRQoL) in cancer patients are often difficult to use in clinical practice. The fatigue visual analogue scale (VAS) provides a simple method to assess fatigue. This study evaluated the correlation between HRQoL and fatigue perceived by cancer patients undergoing chemotherapy. METHODS: This was a non-interventional prospective study of adult cancer patients in France presenting with chemotherapy-induced anaemia (CIA) treated with epoetin alfa (Sandoz). Data were collected using an electronic case report form at study inclusion (T0), after 2-3 chemotherapy cycles (T1) and after 4-6 cycles (T2). RESULTS: The study included 982 patients from September 2015 to October 2017. Overall, there was a negative correlation between fatigue VAS and HRQoL. The overall haemoglobin (Hb) change between T0 and T2 was +17.8 % (± 18.1 %). Fatigue assessed by both patients and physicians showed a clinically significant improvement during the study. Global HRQoL also increased. CONCLUSION: Treatment of CIA with epoetin alfa (Sandoz) improved Hb levels, fatigue, and HRQoL, with a correlation observed between fatigue VAS score and HRQoL. Fatigue VAS could act as a simple alternative to more complex methods to measure HRQoL; however, further analyses are required to confirm this association.

Effects of Exogenous Erythropoietin on Rabbit (Oryctolagus cuniculus) Hematological and Biochemical Parameters.

Rabbits can develop anemia due to serial phlebotomy or secondary to induced disease states. This study evaluated the effects of a single injection and three consecutive injections of erythropoietin in rabbits at 150 IU/kg and 1,000 IU/kg in order to determine whether these dosages produce a sustained increase in hematocrit. Analysis of CBC and chemistry parameters showed significant elevation in hematocrit one week after administration of 1,000 IU/kg erythropoietin for three consecutive days. These results indicate that this dosage regimen can increase hematocrit in apparently healthy, nonanemic rabbits for one week.

An updated meta-analysis on the efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitor treatment of anemia in nondialysis-dependent chronic kidney disease.

BACKGROUND: Renal anemia, a common complication and threat factor of chronic kidney disease (CKD), has long been treated with injectable erythropoietin-stimulating agents (ESAs). As concerns regarding cardiovascular safety and erythropoietin resistance to ESAs have emerged, alternative therapies are urgently needed. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), an oral agent, has been proven to be effective in improving renal anemia. However, the effects of HIF-PHIs on nondialysis-dependent CKD (NDD-CKD) have yet to be supported by updated meta-analyses. METHODS: A meta-analysis of clinical randomized controlled trials (RCTs) on HIF-PHI treatment of NDD-CKD patients based on PubMed, EMBASE, and Cochrane databases as of July 16th, 2023, was conducted. The primary outcomes were the level of hemoglobin (Hb) postintervention and the ratio of Hb responses. Most of the analysis was conducted via RevMan 5.3 software using a random-effects model. Stata (version 15.0) was used to analyze the publication bias. RESULTS: Twenty-two studies with a total of 7178 subjects in the HIF-PHI group, 3501 subjects in the ESA group and 2533 subjects in the placebo group were enrolled. HIF-PHIs increased the level of Hb and improved iron metabolism but were not inferior to ESAs in terms of safety. CONCLUSIONS: HIF-PHIs may be a convenient and safe alternative to ESAs in patients with NDD-CKD and anemia.

Disproportionality Analysis on Hypothyroidism With Roxadustat Using the Japanese Adverse Drug Event Database.

Hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) is a novel agent for the treatment of renal anemia. HIF-PHI increases endogenous erythropoietin production by inhibiting the degradation of an erythropoietin transcription factor. Although beneficial effects are expected from HIF-PHI, its novel mechanism raises concerns regarding the risk of potential adverse events. The cases of hypothyroidism, which had not been reported in clinical trials, were reported after the administration of roxadustat in a real-world setting. However, the effects of HIF-PHIs on thyroid function have not yet been fully evaluated. This study aimed to assess the clinical impact of HIF-PHIs on thyroid function using the Japanese Adverse Drug Event Report database, a spontaneous reporting system in Japan, because HIF-PHIs were made available in Japan before they were available in other countries. Although a disproportionality signal for hypothyroidism was detected with roxadustat (reporting odds ratio [ROR]:22.1, 95% confidence interval [CI]:18.3-26.7, no signals were detected with another HIF-PHI, daprodustat (ROR:1.3, 95%CI:0.3-5.4), and epoetin beta pegol (ROR:1.2, 95%CI:0.5-2.7). Signals of hypothyroidism due to roxadustat were also detected regardless of age or sex. Approximately 50% of hypothyroidism cases were reported within 50 days of starting roxadustat use. These results indicate that roxadustat use may be related to the development of hypothyroidism. The need for monitoring of thyroid function should be alerted during roxadustat administration regardless of age or sex.

Is metabolic-dysfunction-associated fatty liver disease or advanced liver fibrosis associated with erythropoietin stimulating agent hypo-responsiveness among patients with end-stage kidney disease on haemodialysis?

AIM: This study aims to determine if metabolic-dysfunction-associated fatty liver disease (MAFLD) or advanced liver fibrosis is associated with erythropoietin stimulating agent (ESA) hypo-responsiveness in hemodialysis patients. METHODS: In a cross-sectional study of 379 hemodialysis patients, FibroTouch transient elastography was performed on all patients. Erythropoeitin resistance index (ERI) was used to measure the responsiveness to ESA. Patients in the highest tertile of ERI were considered as having ESA hypo-responsiveness. RESULTS: The percentage of patients with ESA hypo-responsiveness who had MAFLD was lower than patients without ESA hypo-responsiveness. FIB-4 index was significantly higher in ESA hypo-responsive patients. In multivariate analysis, female gender (aOR = 3.4, 95% CI = 1.9-6.2, p < 0.001), dialysis duration ≥50 months (aOR = 1.8, 95% CI = 1.1-2.9, p < 0.05), elevated waist circumference (aOR = 0.4, 95% CI = 0.2-0.8, p = 0.005), low platelet (aOR = 2.6, 95% CI 1.3-5.1, p < 0.01), elevated total cholesterol (aOR = 0.5, 95% CI 0.3-0.9, p < 0.05) and low serum iron (aOR = 3.8, 95% CI = 2.3-6.5, p < 0.001) were found to be independent factors associated with ESA hypo-responsiveness. Neither MAFLD nor advanced liver fibrosis was independently associated with ESA hypo-responsiveness. However, every 1 kPA increase in LSM increased the chance of ESA-hyporesponsiveness by 13% (aOR = 1.1, 95% CI = 1.0-1.2, p = 0.002) when UAP and LSM were used instead of presence of MAFLD and advanced liver fibrosis, respectively. CONCLUSION: MAFLD and advanced liver fibrosis were not independently associated with ESA hypo-responsiveness. Nevertheless, higher FIB-4 score in ESA hypo-responsive group and significant association between LSM and ESA hypo-responsiveness suggest that liver fibrosis may be a potential clinical marker of ESA hypo-responsiveness.

Safety of High Dose Erythropoietin Used with Therapeutic Hypothermia as Treatment for Newborn Hypoxic-Ischemic Encephalopathy: Secondary Analysis of the HEAL Randomized Controlled Trial.

OBJECTIVE: To assess whether high dose erythropoietin (Epo) treatment of cooled infants with neonatal hypoxic ischemic encephalopathy results in a higher risk of prespecified serious adverse events (SAEs). STUDY DESIGN: Five hundred infants born at ≥36 weeks of gestation with moderate or severe hypoxic ischemic encephalopathy undergoing therapeutic hypothermia were randomized to Epo or placebo on days 1, 2, 3, 4, and 7. Pretreatment and posttreatment SAEs were compared with adjusted generalized linear models, with posttreatment models adjusted for the presence of a pretreatment SAE. Clinical risk factors and potential mechanisms for SAEs were also examined. RESULTS: The rate of experiencing at least one posttreatment SAE did not significantly differ between groups (adjusted relative risk [aRR], 95% CI: 1.17, 0.92-1.49); however, posttreatment thrombosis was identified more often in the Epo group (n = 6, 2.3%) than the placebo group (n = 1, 0.4%; aRR, 95% CI: 5.09, 1.32-19.64). The rate of posttreatment intracranial hemorrhage identified at the treatment sites by either ultrasound or magnetic resonance imaging was slightly elevated in the Epo group (n = 61, 24%) but not significantly different from the placebo group (n = 46, 19%; aRR, 95% CI: 1.21, 0.85, 1.72). CONCLUSIONS: A small increased risk of major thrombotic events was identified in the Epo treatment group. TRIAL REGISTRATION: NCT02811263.

Treatment satisfaction with molidustat in CKD-related anemia in non-dialysis patients: a post-hoc analysis of two clinical trials.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs. Consequently, erythropoietin-promoting medications, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, have been developed. This study aimed to evaluate changes in the Treatment Satisfaction Questionnaire for Medicine version II (TSQM-II) domain scores relative to baseline in each trial, to assess patient satisfaction with molidustat versus darbepoetin alfa. METHODS: This post-hoc analysis of two clinical trials compared treatment satisfaction with an HIF-PH inhibitor, molidustat, versus a standard ESA, darbepoetin alfa, as part of therapy in patients with non-dialysis chronic kidney disease (CKD) and renal anemia. RESULTS: Exploratory outcome data using the TSQM-II showed that both arms in both trials had enhanced treatment satisfaction over the course of the study period, as well as improvements in most TSQM-II domains at week 24 of treatment. Molidustat was associated with convenience domain scores at multiple time points depending on the trial. More patients were highly satisfied with the convenience of molidustat than that of darbepoetin alfa. Patients treated with molidustat had increased global satisfaction domain scores compared with those treated with darbepoetin alfa; however, the differences in global satisfaction domain scores were not significant. CONCLUSION: These patient-reported satisfaction outcomes support the use of molidustat as a patient-centered treatment option for CKD-related anemia. REGISTRATION OF CLINICAL TRIALS: ClinicalTrials.gov Identifier: NCT03350321 (November 22, 2017). CLINICALTRIALS: gov Identifier: NCT03350347 (November 22, 2017).

Vadadustat for treatment of anemia in patients with dialysis-dependent chronic kidney disease receiving peritoneal dialysis.

BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24-36). RESULTS: Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. CONCLUSIONS: In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.

Comparative Study of Recombinant Human Erythropoietin (rhEPO) Products on CKD (Chronic Kidney Disease) Patients.

PURPOSE: This study was conducted to evaluate whether the efficacy and safety profile of recombinant human erythropoietin (rhEPO) manufactured by Daewoong Pharmaceutical Co., Ltd was similar to biological products approved by the drug safety regulatory authority. PATIENTS AND METHODS: It was an open-label, randomized, comparative, parallel, multi-center study in hemodialysis patients with anemia. The reference product at an individualized dose 3 times a week was given in 4-8 weeks of titration period and hemoglobin (Hb) level was controlled to reach the range of 10-12 g/dL. Then, the subjects were randomly administered with reference or test product with the same dose regimen. The primary endpoints were to demonstrate the Hb level change between baseline and evaluation period in both treatment groups, while the secondary endpoints were the mean change in weekly dosage per kg body weight and the instability rate of Hb level during maintenance and evaluation period. The safety was evaluated based on the adverse events incidence. RESULTS: There was no statistical difference in the change of Hb between test and reference (0.14 g/dL and 0.75 g/dL respectively, with p>0.05), also for the mean changes of weekly dosage between groups (1091.40 IU and 570.15 IU respectively, with p>0.05). The instability rate of Hb in both test and reference was not statistically significantly different as well (26 and 15% respectively, with p>0.05). CONCLUSION: This study proves that the efficacy indicated by the change instability of Hb and safety indicated by adverse event incidence of Epodion and the reference product on chronic kidney disease were similar.

Extremely Low Dose of Erythropoiesis-Stimulating Agent May Be Associated with Increased Mortality in Hemodialysis Patients.

INTRODUCTION: Although high-dose erythropoiesis-stimulating agent (ESA) has been shown to increase mortality risk and adverse cardiovascular events in hemodialysis patients, the safety of extremely low-dose ESA is unclear. METHODS: We retrospectively analyzed the association between ESA dose and mortality in the monthly dosing range of 0-43,000 U of equivalent epoetin alfa in 304 Taiwan hemodialysis patients by using Cox proportional hazard model and cubic spline model. RESULTS: Compared with mean monthly ESA dose of 15,000-25,000 U (mean ± standard deviation 20,609 ± 2,662 U), monthly ESA dose of less than 15,000 U (mean ± standard deviation 7,413 ± 4,510 U) is associated with increased mortality. Monthly ESA dose of 25,001-43,000 U (mean ± standard deviation 31,160 ± 4,304 U) is not associated with higher mortality risk than monthly ESA dose of 15,000-25,000 U. The results were consistent in Cox proportional hazard models and cubic spline models. Subgroup analyses showed no significant heterogeneities among prespecified subgroups. CONCLUSIONS: Extremely low dose of ESA in hemodialysis patients may be associated with increased mortality risk. Future studies are warranted to prove this association.

Long-Term Efficacy of Erythropoiesis-Stimulating Agents in Patients with Low-Risk or Intermediate-1-Risk Myelodysplastic Syndrome: Multicenter Real-Life Data

Objective: This study was undertaken to evaluate the long-term clinical efficacy of epoetin alfa and darbepoetin alfa in patients with myelodysplastic syndrome (MDS) in a real-life setting. Materials and Methods: A total of 204 patients with low-risk or intermediate-1-risk MDS who received epoetin alfa or darbepoetin alfa were included. Hemoglobin levels and transfusion needs were recorded before treatment and at 12 months, 24 months, 36 months, and 48 months of treatment. Results: At the 36-month (p=0.025) and 48-month (p=0.022) visits, epoetin alfa yielded significantly higher hemoglobin levels compared to darbepoetin alfa. Transfusion needs were also significantly lower with epoetin alfa compared to darbepoetin alfa at 24 months (p=0.012) and in the low-risk group compared to the intermediate-risk group at 24 months (p=0.018), 36 months (p=0.025), and 48 months (p<0.001). Treatment response rates at the 24-month, 36-month, and 48-month visits in the epoetin alfa (43.0%, 33.6%, and 27.1%), darbepoetin alfa (29.9%, 22.7%, and 16.5%), low-risk (39.3%, 30.0%, and 26.0%), and intermediate-risk (29.6%, 24.1%, and 11.1%) groups were lower than those obtained at 12 months, and the values differed significantly for the 36-month and 48-month visits with values ranging from p<0.05 to p<0.001. Conclusion: This real-life long-term ESA extension study investigated the clinical efficacy of epoetin alfa and darbepoetin alfa for up to 48 months, revealing that treatment efficacy reached a plateau starting from the 24th month of therapy with a continuing decrease in treatment response rates regardless of treatment type, risk status, or gender. Nonetheless, significantly higher hemoglobin levels and marked improvement in transfusion needs were evident in epoetin-treated patients compared to darbepoetin-treated patients and in the low-risk group compared to the intermediate-risk group.

Novel Finding of Urinary Erythropoietin as an Early Biomarker of Cisplatin-Induced Nephrotoxicity.

Cisplatin is a chemotherapeutic drug used to treat a great variety of solid tumors. Its dose is commonly limited by its nephrotoxicity, manifested as acute kidney injury (AKI). Erythropoietin (Epo) is a glycoprotein hormone that regulates the production of red blood cells. This study was performed to evaluate the presence of endogenous Epo in male Wistar rat urine and to analyse changes in urinary Epo levels in response to cisplatin- induced AKI. Dose-dependent studies and time-dependent experiments were performed to evaluate changes in urea nitrogen and creatinine in plasma as well as Epo, neutrophil gelatinase-associated lipocalin (NGAL), alkaline phosphatase (AP) activity, creatinine and total proteins in urine at 2 days post-dosing. Rats received 2, 5 or 10 mg/kg b.w., i.p. of cisplatin. At 5 mg/kg b.w., i.p. cisplatin, significant increases in urinary Epo were detected. Significant increases in urea nitrogen and creatinine in plasma, NGAL, AP, proteins, and Epo were observed in urine from rats that received 10 mg/kg b.w., i.p. of cisplatin. In the time-dependent experiments, rats were injected with a dose of 5 mg/kg b.w., i.p. of cisplatin, and sampling occurred 2, 4, and 14 days post-dosing. In these animals, there were significant increases in urea nitrogen and creatinine in plasma and total proteins, AP activity, Epo, and NGAL in urine on day 4. Urinary Epo was also detected on day 2. Taken together, these findings provide weight of evidence for urinary Epo as a promising early biomarker of cisplatin-induced AKI in male rats.

An animal model of EPO-induced abdominal aortic aneurysm in WT and Apoe-/- mice.

Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease, but the underlying mechanisms remain obscure. Here, we provide a protocol using erythropoietin (EPO) to induce the formation of AAA in both wild-type (WT) and apolipoprotein E (Apoe-/-) mice. We describe the dose, manner, and timing of EPO administration. We also detail mice dissection, aorta isolation, and histological analysis. The animal model of EPO-induced AAA provides a useful tool for exploring the mechanism of AAA in experimental studies. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021).1.

Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents-post hoc analyses of the ASCEND-ND and ASCEND-D trials.

BACKGROUND: The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305). METHODS: ASCEND-ND randomized 3872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2964 patients to daprodustat or conventional erythropoiesis-stimulating agents (ESAs). In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date + 1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at last dose date, last dose date + dosing intervals, or end of study). RESULTS: In ASCEND-ND, the safety of daprodustat vs darbepoetin on cancer-related AEs depended on the duration of follow-up after last dose date: hazard ratio (HR) 1.04 [95% confidence interval (CI) 0.77, 1.40] at end of study [HR 1.12 (95% CI 0.81, 1.56) for last dose date + dosing interval; HR 1.50 (95% CI 1.04, 2.15) for last dose date + 1 day]. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined. CONCLUSIONS: Prespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat. TRIAL REGISTRATION: The ASCEND-ND trial is registered with ClinicalTrials.gov (NCT02876835); the ASCEND-D trial is registered with ClinicalTrials.gov (NCT02879305).

Effect of erythropoiesis-stimulating agents on breast cancer patients: a meta-analysis.

Erythropoiesis-stimulating agents (ESAs) have been reported to increase the risk of death in cancer patients. In this study, we selected breast cancer, which is currently the most prevalent cancer worldwide, for a meta-analysis to re-examine the advantages and disadvantages of using ESAs. All relevant studies were searched by PubMed, Embase, Web of science, and Cochrane Library. Endpoints including mortality, incidence of thrombo-vascular events, hemoglobin, and transfusion requirements were meta-analyzed based on random-effects model or fixed-effect model. 10 studies were finally included, with a total sample size of 6785 patients. The risk of mortality was higher in patients using ESA than in controls (RR 1.07, 95% CI 1.01-1.13, P = 0.03); subgroup analysis found that the mortality rate was higher in patients treating with ESA for > 6 months (RR 1.27, 95% CI 1.05-1.55, P = 0.01) and epoetin α (RR 1.07, 95% CI 1.01-1.14, P = 0.03). The incidence of thrombo-vascular adverse events was higher in patients using ESA than in controls (RR 1.53, 95% CI 1.27-1.86, P < 0.0001). The ESA group was more effective in improving anemia in cancer patients (MD 1.20, 95% CI 0.77-1.63, P < 0.00001). The blood transfusion needs of patients in the ESA group were significantly lower (RR 0.52, 95%CI 0.44-0.60, P < 0.00001). There was no statistically significant difference between the two groups in disease progression-related conditions (HR 1.03, 95%CI 0.95-1.12, P = 0.52). ESAs increase the risk of mortality and the incidence of thrombo-vascular adverse events in breast cancer patients, while reducing their anemia symptoms and transfusion requirements. Registration PROSPERO CRD42022330450.